Genotype–Phenotype Correlations in Patients with STAT1 Gain-of-Function Mutations: A Case Series

Introduction STAT1 gain-of-function (GOF) mutations result in a broad clinical spectrum characterized by complex phenotypic manifestations. In addition to the hallmark chronic mucocutaneous candidiasis (CMC), patients are predisposed to bacterial and viral infections, autoimmunity, endocrinopathies, lymphoproliferative disorders, and malignancies. Severe complications, including invasive infections, cerebral aneurysms, and malignancies, are significant predictors of poor outcomes. Understanding genotype–phenotype correlations is critical for optimizing management in this challenging patient population. Methods We conducted a retrospective review of electronic medical records for five patients diagnosed with STAT1 GOF mutations at Mayo Clinic, Rochester, MN. This case series included data on demographics, clinical history, immunologic evaluations, genetic testing results, disease manifestations, treatments, and outcomes. Results The cohort included five patients (1 male, 4 females; mean age at diagnosis: 21.7 years) with heterozygous STAT1 GOF mutations. Three patients had c.1154C>T (p.Thr385Met), one had c.1310C>T (p.Thr437Ile) in the DNA-binding domain (DBD), and one had c.856A>G (p.Lys286Glu) in the coiled-coil domain (CCD). Universal features included CMC and recurrent sinopulmonary infections. Patients with c.1154C>T presented with early-onset infections, severe autoimmunity (e.g., pancytopenia and enteropathy), and bronchiectasis, requiring ruxolitinib in all three cases. The patient with c.1310C>T had a late childhood onset of symptoms, later complicated by persistent histoplasmosis. The c.856A>G case experienced severe multidrug-resistant infections, splenomegaly, coagulopathy, neurological complications, poor response to ruxolitinib, and died from complications of MSSA pneumonia and monkeypox. Conclusion Genotype–phenotype correlations in STAT1 GOF mutations highlight a diverse clinical spectrum driven by mutation-specific mechanisms. DBD mutations are associated with more severe outcomes, including early-onset immunodeficiency, invasive infections, and autoimmunity, due to faster nuclear accumulation and impaired dephosphorylation of STAT1. CCD mutations present with multisystem involvement, further emphasizing the heterogeneity of clinical manifestations. These variations underscore the importance of genetic insights for prognostication and tailored management. Early interventions, including hematopoietic stem cell transplantation for severe cases, and emerging therapies like JAK inhibitors show promise; however, ruxolitinib's need for individualized dosing, vigilant monitoring, continuous treatment to maintain benefits, and lack of epigenetic correction warrant further evaluation.